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Megakaryoblastic Leukemia 1, a Potent Transcriptional Coactivator for Serum Response Factor (SRF), Is Required for Serum Induction of SRF Target Genes
- Source :
- Molecular and Cellular Biology. 23:6597-6608
- Publication Year :
- 2003
- Publisher :
- Informa UK Limited, 2003.
-
Abstract
- Megakaryoblastic leukemia 1 (MKL1) is a myocardin-related transcription factor that we found strongly activated serum response element (SRE)-dependent reporter genes through its direct binding to serum response factor (SRF). The c-fos SRE is regulated by mitogen-activated protein kinase phosphorylation of ternary complex factor (TCF) but is also regulated by a RhoA-dependent pathway. The mechanism of this pathway is unclear. Since MKL1 (also known as MAL, BSAC, and MRTF-A) is broadly expressed, we assessed its role in serum induction of c-fos and other SRE-regulated genes with a dominant negative MKL1 mutant (DN-MKL1) and RNA interference (RNAi). We found that DN-MKL1 and RNAi specifically blocked SRE-dependent reporter gene activation by serum and RhoA. Complete inhibition by RNAi required the additional inhibition of the related factor MKL2 (MRTF-B), showing the redundancy of these factors. DN-MKL1 reduced the late stage of serum induction of endogenous c-fos expression, suggesting that the TCF- and RhoA-dependent pathways contribute to temporally distinct phases of c-fos expression. Furthermore, serum induction of two TCF-independent SRE target genes, SRF and vinculin, was nearly completely blocked by DN-MKL1. Finally, the RBM15-MKL1 fusion protein formed by the t(1;22) translocation of acute megakaryoblastic leukemia had a markedly increased ability to activate SRE reporter genes, suggesting that its activation of SRF target genes may contribute to leukemogenesis.
- Subjects :
- Transcriptional Activation
Serum Response Factor
RHOA
Oncogene Proteins, Fusion
Biology
Mice
Acute megakaryoblastic leukemia
Genes, Reporter
RNA interference
Serum response factor
medicine
Animals
Humans
Molecular Biology
Transcription factor
Cells, Cultured
Genes, Dominant
Transcriptional Regulation
Reporter gene
Genes, fos
RNA-Binding Proteins
Cell Biology
medicine.disease
Serum Response Element
Molecular biology
Fusion protein
Protein Structure, Tertiary
DNA-Binding Proteins
Gene Expression Regulation
Trans-Activators
biology.protein
RNA Interference
rhoA GTP-Binding Protein
Transcription Factors
Subjects
Details
- ISSN :
- 10985549
- Volume :
- 23
- Database :
- OpenAIRE
- Journal :
- Molecular and Cellular Biology
- Accession number :
- edsair.doi.dedup.....3c504b77557379391586972a664bd71f